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Polo-Like Kinases in Colorectal Cancer: Potential for Targeted Therapy

  • Molecular Biology (S Anant, Section Editor)
  • Published:
Current Colorectal Cancer Reports

Abstract

The five individual members of the mammalian polo-like kinase family play non-redundant roles in centriole replication and maturation, mitotic progression, cytokinesis, and the DNA damage response. In human colorectal cancer, Plk1 and Plk4 are expressed at higher levels in tumor than adjacent normal mucosa, and the degree of overexpression correlates with adverse prognosis. In colorectal cancer cell lines, suppression of Plk1 activity leads to mitotic arrest and apoptosis, while inhibition of Plk4 activity reduces tumor growth and invasion. Inhibition of Plk1 or Plk4 in mice using orally bioavailable agents reduces the growth of human colorectal cancer xenografts. On the basis of these preclinical studies, clinical trials of several different targeted anti-Plk1 agents have been undertaken in patients with advanced solid tumors, and a phase I trial of the anti-Plk4 inhibitor CFI-400945 is currently accruing. Here, we review the rationale, results, and potential limitations of Plks as therapeutic targets. Evidence from genetic mouse models suggests that Plk1, Plk2, Plk3, and Plk4 may all possess tumor suppressive activity, particularly with aging. Thus, enthusiasm for the use of targeted Plk inhibitors in cancer therapy must be tempered somewhat by the potential for development of second primary tumors in the long term.

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Karineh Kazazian, Olga Brashavitskaya, Francis S.W. Zih, David Berger-Richardson, Roland S.Z. Xu, Karina Pacholczyk, Jennifer Macmillan, and Carol J. Swallow declare that they have no conflict of interest.

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  1. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada, M5G 1X5

    Karineh Kazazian, Olga Brashavitskaya, Francis S. W. Zih, David Berger-Richardson, Roland S. Z. Xu, Karina Pacholczyk & Carol J. Swallow

  2. Department of Surgery, University of Toronto, Toronto, Ontario, Canada

    Karineh Kazazian, Francis S. W. Zih, David Berger-Richardson, Jennifer Macmillan & Carol J. Swallow

  3. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Karineh Kazazian, Francis S. W. Zih, David Berger-Richardson & Carol J. Swallow

  4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Olga Brashavitskaya & Carol J. Swallow

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Kazazian, K., Brashavitskaya, O., Zih, F.S.W. et al. Polo-Like Kinases in Colorectal Cancer: Potential for Targeted Therapy. Curr Colorectal Cancer Rep 11, 187–199 (2015). https://doi.org/10.1007/s11888-015-0275-4

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